Lysosomes are involved in a wide variety of physiological and pathological processes. Recent studies have focused on the genetic storage disorders in which a lysosomal enzyme is absent and lysosomes become enlarged with undegraded metabolic products. Chediak-Higashi syndrome is another congenital disorder in which lysosomes are abnormally enlarged in a variety of cell types. However, this appears not to be due to an enzyme deletion but to an alteration in the metabolism of lipid or other substances that leads, secondarily, to lysosome enlargement. Previous studies in our laboratory on the beige mouse, a homologue of the human disorder, indicate that abnormal lysosomes originate from a specialized region of smooth endoplasmic reticulum. They also suggest that disturbances in synthesis or degradation of lipid may underly this disorder. Our proposal is aimed at establishing the mechanisms whereby a single genetic change affects the lysosomes of many cell types. Electron microscopy correlated with cytochemical methods for enzyme activities will be applied to the study of lysosome formation in specific cell types. Functional studies will include assessment of phagocytosis and degranulation in vitro in granulocytic leukocytes and macrophages. These investigations may provide information on the processes of lysosome formation as well as the role of lysosomes in pathogenesis.